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Diagnosis of myeloma related disorders
Dr. Paul Mellor, DECVIM

Complete investigations for myeloma related disorders are complex and may take several days. Ideally, referral to a multi-disciplinary specialist centre is in the best interests of the patient. Work-up may include:

Tests What to look for
Ophthalmological exams Retinal haemorrhage, retinal vessel distension and tortuosity, aneurysms.
Blood pressure Appropriate ocular signs in the absence of hypertension is consistent with hyperviscosity syndrome.
Haematology Anaemia, thrombocytopenia, myeloma cells in peripheral blood.
Biochemistry Hyperglobulinaemia, azotaemia, hypercalcaemia, liver function.
Serum gammopathy Serum protein electrophoresis and immunoelectrophoresis or immunofixation - allowing quantification of the paraprotein concentration as well as the identify of the heavy chain type.
Immunoglobulin profile IgA, IgG and IgM quantification.
Urinalysis White cell count, bacteria.
Urine immunoglobulin light chains Urine protein electrophoresis or Bence-Jones precipitation or immunofixation.
Urine protein : creatinine ratio A high UPC combined with evidence of urine immunoglobulin light chains is highly suggestive of renal amyloidosis.
Survey skeletal radiographs Lytic lesions, osteoporosis, compression fractures (CT may help clarify certain cases) have been reported in the cat, but appear to be uncommon in comparison to myeloma in man
Survey abdominal radiographs Organ enlargement / masses.
Abdominal ultrasonography Enlargement / distortion of normal organ architecture (in particular of the liver / spleen) or the presence of masses.
Further imaging studies (e.g. MRI or CT) May be indicated to delineate abnormalities or tumour masses more accurately
Coagulation profiles prior to biopsy Thrombocytopathia and altered coagulation times as a result of hyperglobulinaemia.
Cytology Bone marrow aspirate, fine needle aspirates of abnormal organs, masses or the liver or spleen. B cell morphology.
Histopathology Bone marrow core, tissue biopsy of abnormal organs / masses. B cell morphology.
Histochemistry Exclusion of other round cell tumour types. Diagnosis of amyloid.
Immuno histo- or cyto- chemistry Expression of a single light or heavy chain type to exclude reactive plasma cell lesions is a critically important part of the diagnostic process.

Diagnosis should be based on accurate histopathological / cytological classification & immunolabelling preferably alongside the demonstration of a paraproteinaemia where relevant / possible. In our series, the histopathological diagnosis was given primacy over the cytological diagnosis on the basis that exams of repeat sections of tissue were more likely to be representative than cytological slides alone. The confidence in a cytological diagnosis will be enhanced with either immunocytochemistry and/or concurrent tissue biopsy. A cytological / histopathological diagnosis of lymphoma is allowed as an MRD, so long as there is a paraproteinaemia as evidenced by eg serum protein electrophoresis.

Defining plasma cells, plasma cell pathology including MRDs

What are plasma cells ? To answer this, an understanding of normal B cell development is necessary. The normal physiological development of the mammalian B lymphocyte commences in the bone marrow. Here, the pre-B cell undergoes re-arrangement of its heavy- and light- chain immunoglobulin (IgH and IgL) genes resulting in the expression of surface IgM. Upon further maturation, the naïve B lymphocyte migrates to secondary lymphoid tissues where stimulation with antigen and the provision of T cell help leads to its proliferation and differentiation into plasmablasts. These form either IgM secreting plasma cells, many (but not all) of which have a short lifespan in the periphery, or they enter lymphoid follicular centres. In lymph node or splenic germinal centres, the plasmablasts undergo active somatic hypermutation of the IgH and IgL gene sequences resulting in an antigen-selected clone that expresses high affinity immunoglobulin. Some are released into blood as lymphoplasmacyte memory cells, whereas others switch immunoglobulin isotype from IgM to IgG, IgA or IgE. The full morphological and functional transition to a terminally-differentiated plasma cell occurs after exiting the germinal centre and appears to be associated with migration into new microenvironments. In man, the principal site is the bone marrow, but studies in rodents have identified five other key sites: splenic red pulp, lymph node medullary cords, gastro-intestinal tract, respiratory tract and inflamed tissues (Potter 2003, Seidl et al 2003).

What are myeloma cells ? Myeloma cells are neoplastically transformed plasma cells. From cytogenetic and molecular studies in human myeloma patients and mouse myeloma models, a multi-step model of the evolution of myeloma has been hypothesized. An early event is chromosomal translocation in the immunoglobulin heavy chain site, leading to the immortalization of a plasma cell clone. A potential clinical manifestation of this event is monoclonal gammopathy of unknown significance (MGUS). The condition is denoted by the presence of a serum monoclonal protein (M-protein or paraprotein) in the absence of significant infiltration of the bone marrow or extramedullary tissues by plasma cells. This is a well recognized disorder in man that is clinically associated with an increased risk of developing multiple myeloma (Kyle 1993). Molecular studies have confirmed that further chromosomal changes, including deletions of genes and / or activation of oncogenes, allows the creation of a neoplastic plasma cell (Seidl et al 2003). Recent work has suggested that myeloma cells are derived from a stem cell tumourogenic clone (Matsui et al 2004).

Myeloma (neoplastic plasma cells) can be differentiated from normal plasma cells and other non-cancerous plasma cell lesions (e.g. reactive plasma cell lesions in a variety of tissues including lymphocytic-plasmacytic stomatitis, lymphocytic-plasmacytic dermatopathies and plasma cell granulomas) with the aid of cytology, histopathology and more specifically by immuno-labeling (as a surrogate indicator of monoclonality), cytogenetic and molecular studies.

MRD include the following:

1) Multiple Myeloma
Multiple myeloma is the archetypal MRD, and the diagnostic criteria in dogs and humans includes the presence of myeloma cells in bone marrow accompanied by 1 or more of the following: (1) serum paraproteinemia (2) immunoglobulin light chain (Bence-Jones) proteinuria or (3) osteolytic bone lesions (The-UK-Myeloma-Forum 2001, Vail 2001). Historically, the same diagnostic criteria have been applied to the cat and a diverse array of sometimes confusing terminology and diagnostic criteria have been used to describe the disease including multiple myeloma, myeloma, plasma cell dyscrasia, reticulum cell myeloma, plasma cell sarcoma and plasma cell tumour (Holzworth and Meier 1957, Farrow and Penny 1971, Mitcham et al 1985, Harbison 1987, Morrison 2002). Recent work has shown that radiographic bone lesions are uncommon in the cat (8% versus 80% of human MRD patients, P<0.001) and that extramedullary involvement at initial presentation is very common (67% versus 5% of human MRD patients, P<0.001) (Mellor et al 2006). The extramedullary involvement is typically manifested by splenomegaly or hepatomegaly or skin masses although a diverse range of other organs can be involved. Therefore in cats, we have avoided the term “multiple myeloma” and have instead used the term 'myeloma' to denote plasma cell neoplasia occurring in an intra-medullary or intra- plus extra-medullary location(s) (Mellor et al 2006).

2) Extramedullary plasmacytoma (EMP)
EMP is defined as myeloma cell infiltration in soft tissue without primary evidence of bone marrow involvement and can be divided into cutaneous (CEMP) and non-cutaneous (NCEMP) forms.

In human and canine CEMP, the disease is usually unaccompanied by systemic clinical signs, typicially follows a benign course and excision is curative (Clark et al 1992, Soutar et al 2004). Occasional feline CEMP cases follow a similar course (Mellor et al 2006). However in feline CEMP, the majority of reported cases had a paraproteinaemia; suffered rapid tumour development and had evidence of multi-organ and bone marrow myeloma cell infiltration (Dust et al 1982, Harbison 1987, Carothers et al 1989, Radhakrishnan et al 2004, Mellor et al 2006).

All reported NCEMP feline cases have had signs of systemic disease attributable to a paraproteinaemia and / or metastatic behaviour (Williams and Goldschmidt 1982, Harbison 1987, Mandel and Esplin 1994, Ward et al 1997, Zikes et al 1998, Michau et al 2003, Mellor et al 2006). Typically, the liver and/or spleen were infiltrated. Other locations have included the kidneys, gastro-intestinal tract, lymph nodes, stomach, epidura, orbit, iris and retroperitoneal space.

3) Solitary plasmacytoma of bone (SPB)
SPB is a rare MRD. SPB exhibits different neoplastic behaviour relative to EMPs or myeloma. In people for example, over 60% of patients with SPB have a paraprotein, whereas <25% of EMP patients have a demonstrable paraprotein by standard electrophoretic techniques. And over 75% of SBP human patients will go on to develop multiple myeloma (versus <30% of EMP patients) (Soutar et al 2004). The diagnosis is based on the demonstration of a single area of bone destruction due to clonal myeloma cells, verified by complete skeletal survey (radiographic, or even more sensitively MRI), additional bone marrow aspiration and core biopsy at a separate site to demonstrate cytologically and histopathologically normal marrow elsewhere (<5% plasma cells) as well as no clinico-pathological or imaging evidence of myeloma cell involvement in other locations (Mackey 1977, Soutar et al 2004). SPB has been described in two cats (Mellor et al 2007b).

4) Waldenström (IgM) macroglobulinemia
IgM macroglobulinaemia is characterized by the infiltration of bone marrow and/or other organs by plasmacytoid lymphocytes that secrete an IgM paraprotein. The new World Health Organization classification, places WM under the category of lymphoplasmacytic lymphomas, a subcategory of the low-grade, non-Hodgkin lymphomas (Harris et al 2000). However, there remain strong reasons on clinical and neoplastic natural history grounds to consider WM as an MRD, including it's ability to cause hyperviscosity syndrome. WM has been described in two cats (MacEwen and Hurvitz 1977, Williams and Goldschmidt 1982).

5) Immunoglobulin secreting lymphoma
Ig secreting lymphoma has been reported in two cats (Dust et al 1982, Mellor et al 2006). The cytological / histopathological appearance of these cases is of lymphoma (as opposed to a myeloma cell / plasmacytoid appearance) but there is hyperglobulinaemia and a demonstrable paraproteinaemia by serum protein electrophoresis.

6) Myeloma cell leukaemia
Abnormal numbers of myeloma cells in peripheral blood is designated myeloma cell leukaemia. It has been reported in three cats (Engle and Brody 1969, Radhakrishnan et al 2004, Patel et al 2005).

Notes on hyperglobulinaemia and paraproteinaemia
Absolute hyperglobulinaemia (also known as a gammopathy) is a result of an increase in beta- or gamma- globulins. Gammopathies can be polyclonal or monoclonal. Polyclonal increases result from chronic antigenic stimulation. Monoclonal / biclonal gammopathies can arise through neoplastic or non-neoplastic diseases. A monoclonal (or less commonly biclonal) gammopathy attributable to neoplastic B cell development is also known as a paraproteinaemia. In the original Mayo clinic series of human patients with monoclonal gammopathy of unknown signficance (MGUS), around a quarter of patients developed an MRD with an actuarial rate of 16% at 10 years rising to 40% by 25 years following detection (Kyle 1993).

MGUS has been reported in the cat, although the level of detailed case investigation has varied - so it is not always possible to determine whether EMP, or other MRD, or non-neoplastic conditions were absolutely excluded (MacEwen and Hurvitz 1977, Patel et al 2005). MGUS have been reported in a number of non-neoplastic conditions in the dog (leishmaniasis, ehrlichiosis, chronic pyoderma) (Burkhard et al 1995, Giraudel et al 2002). This is not an area that is well reported in the cat at this time. In the cat, there are poorly described possible cases of FIP in association with a monoclonal gammopathy (MacEwen and Hurvitz 1977, Hanna 2005). Immunohistochemical demonstration of single Ig light chain expression was not reported in these cases.

Table of Contents
The Veterinary Myeloma Website
Dr. Paul Mellor, DECVIM
What are myeloma related disorders
Clinical signs
Imaging Findings
Clinico-pathological Findings
Anatomical Pathology
Cytology, Histopathology
Other Images
Mis-diagnosis of MRD
Treatment and Survival
Clinical Research & Trials
MRD References
History, Acknowledgements, Links

Date Published: May 21, 2007 Paul Mellor ©

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